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De novo mutations in folate-related genes associated with common developmental disorders

Folate deficiency is an environmental risk factor for several developmental disorders. De novo mutations (DNMs) also play important etiological roles in various developmental disorders. However, it remains unclear whether DNMs in folate-related genes (FRGs) contribute to developmental disorders. We...

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Autores principales: Luo, Tengfei, Li, Kuokuo, Ling, Zhengbao, Zhao, Guihu, Li, Bin, Wang, Zheng, Wang, Xiaomeng, Han, Ying, Xia, Lu, Zhang, Yi, Zhou, Qiao, Fang, Zhenghuan, Wang, Yijing, Chen, Qian, Zhou, Xun, Pan, Hongxu, Zhao, Yuwen, Wang, Yige, Dong, Lijie, Huang, Yuanfeng, Hu, Zhengmao, Pan, Qian, Xia, Kun, Li, Jinchen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Research Network of Computational and Structural Biotechnology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966843/
https://www.ncbi.nlm.nih.gov/pubmed/33777337
http://dx.doi.org/10.1016/j.csbj.2021.02.011
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author Luo, Tengfei
Li, Kuokuo
Ling, Zhengbao
Zhao, Guihu
Li, Bin
Wang, Zheng
Wang, Xiaomeng
Han, Ying
Xia, Lu
Zhang, Yi
Zhou, Qiao
Fang, Zhenghuan
Wang, Yijing
Chen, Qian
Zhou, Xun
Pan, Hongxu
Zhao, Yuwen
Wang, Yige
Dong, Lijie
Huang, Yuanfeng
Hu, Zhengmao
Pan, Qian
Xia, Kun
Li, Jinchen
author_facet Luo, Tengfei
Li, Kuokuo
Ling, Zhengbao
Zhao, Guihu
Li, Bin
Wang, Zheng
Wang, Xiaomeng
Han, Ying
Xia, Lu
Zhang, Yi
Zhou, Qiao
Fang, Zhenghuan
Wang, Yijing
Chen, Qian
Zhou, Xun
Pan, Hongxu
Zhao, Yuwen
Wang, Yige
Dong, Lijie
Huang, Yuanfeng
Hu, Zhengmao
Pan, Qian
Xia, Kun
Li, Jinchen
author_sort Luo, Tengfei
collection PubMed
description Folate deficiency is an environmental risk factor for several developmental disorders. De novo mutations (DNMs) also play important etiological roles in various developmental disorders. However, it remains unclear whether DNMs in folate-related genes (FRGs) contribute to developmental disorders. We obtained a list of 1,821 FRGs from folate metabolism pathways and the Comparative Toxicogenomics Database, along with data concerning DNMs in 15,404 cases and 3,391 controls from the Gene4Denovo database. We used a TADA-Denovo model to prioritize candidate disease-associated FRGs, and characterized these genes in terms of genic intolerance, functional networks, and expression patterns. Compared with the controls, FRGs were significantly enriched in likely damaging DNMs (ldDNMs) in patients with developmental disorders (1.54 ≤ odds ratio ≤ 3.39, P(adj) ≤ 0.0075). Furthermore, FRGs with ldDNMs rather than with likely non-damaging DNMs (lndDNMs) overlapped significantly among the five developmental disorders included in the datasets. The TADA-Denovo model prioritized 96 candidate disease-associated FRGs, which were intolerant to genetic variants. Their functional networks mainly involved pathways associated with chromatin modification, organ development, and signal transduction pathways. DNMT3A, KMT2B, KMT2C, and YY1 emerged as hub FRGs from the protein–protein interaction network. These candidate disease-associated FRGs are preferentially expressed in the excitatory neurones during embryonic development, and in the cortex, cerebellum, striatum, and amygdala during foetal development. Overall, these findings show that DNMs in FRGs are associated with the risk of developmental disorders. Further research on these DNMs may facilitate the discovery of developmental disorder biomarkers and therapeutic targets, enabling detailed, personalized, and precise folate treatment plan.
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spelling pubmed-79668432021-03-25 De novo mutations in folate-related genes associated with common developmental disorders Luo, Tengfei Li, Kuokuo Ling, Zhengbao Zhao, Guihu Li, Bin Wang, Zheng Wang, Xiaomeng Han, Ying Xia, Lu Zhang, Yi Zhou, Qiao Fang, Zhenghuan Wang, Yijing Chen, Qian Zhou, Xun Pan, Hongxu Zhao, Yuwen Wang, Yige Dong, Lijie Huang, Yuanfeng Hu, Zhengmao Pan, Qian Xia, Kun Li, Jinchen Comput Struct Biotechnol J Research Article Folate deficiency is an environmental risk factor for several developmental disorders. De novo mutations (DNMs) also play important etiological roles in various developmental disorders. However, it remains unclear whether DNMs in folate-related genes (FRGs) contribute to developmental disorders. We obtained a list of 1,821 FRGs from folate metabolism pathways and the Comparative Toxicogenomics Database, along with data concerning DNMs in 15,404 cases and 3,391 controls from the Gene4Denovo database. We used a TADA-Denovo model to prioritize candidate disease-associated FRGs, and characterized these genes in terms of genic intolerance, functional networks, and expression patterns. Compared with the controls, FRGs were significantly enriched in likely damaging DNMs (ldDNMs) in patients with developmental disorders (1.54 ≤ odds ratio ≤ 3.39, P(adj) ≤ 0.0075). Furthermore, FRGs with ldDNMs rather than with likely non-damaging DNMs (lndDNMs) overlapped significantly among the five developmental disorders included in the datasets. The TADA-Denovo model prioritized 96 candidate disease-associated FRGs, which were intolerant to genetic variants. Their functional networks mainly involved pathways associated with chromatin modification, organ development, and signal transduction pathways. DNMT3A, KMT2B, KMT2C, and YY1 emerged as hub FRGs from the protein–protein interaction network. These candidate disease-associated FRGs are preferentially expressed in the excitatory neurones during embryonic development, and in the cortex, cerebellum, striatum, and amygdala during foetal development. Overall, these findings show that DNMs in FRGs are associated with the risk of developmental disorders. Further research on these DNMs may facilitate the discovery of developmental disorder biomarkers and therapeutic targets, enabling detailed, personalized, and precise folate treatment plan. Research Network of Computational and Structural Biotechnology 2021-03-01 /pmc/articles/PMC7966843/ /pubmed/33777337 http://dx.doi.org/10.1016/j.csbj.2021.02.011 Text en © 2021 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Article
Luo, Tengfei
Li, Kuokuo
Ling, Zhengbao
Zhao, Guihu
Li, Bin
Wang, Zheng
Wang, Xiaomeng
Han, Ying
Xia, Lu
Zhang, Yi
Zhou, Qiao
Fang, Zhenghuan
Wang, Yijing
Chen, Qian
Zhou, Xun
Pan, Hongxu
Zhao, Yuwen
Wang, Yige
Dong, Lijie
Huang, Yuanfeng
Hu, Zhengmao
Pan, Qian
Xia, Kun
Li, Jinchen
De novo mutations in folate-related genes associated with common developmental disorders
title De novo mutations in folate-related genes associated with common developmental disorders
title_full De novo mutations in folate-related genes associated with common developmental disorders
title_fullStr De novo mutations in folate-related genes associated with common developmental disorders
title_full_unstemmed De novo mutations in folate-related genes associated with common developmental disorders
title_short De novo mutations in folate-related genes associated with common developmental disorders
title_sort de novo mutations in folate-related genes associated with common developmental disorders
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966843/
https://www.ncbi.nlm.nih.gov/pubmed/33777337
http://dx.doi.org/10.1016/j.csbj.2021.02.011
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